Abstract 3720: Cardiac-specific Deletion of Acetyl-CoA Carboxylase 2 (ACC2) Maintains Fatty Acid Oxidation and Left Ventricular Function During Pressure-overload Hypertrophy
Hypertrophied and failing hearts shift to a fetal metabolic profile where decreased fatty acid oxidation (FAO) is coupled with an increased reliance on glucose to satisfy energy demands. To understand the functional significance of the metabolic switch, we sought to maintain FAO, via a cardiac-specific deletion of acetyl CoA carboxylase (ACC2H−/−), in a mouse model of pressure-overload hypertrophy. ACC2H−/− mice were born in the expected Mendelian ratios and deletion of ACC2 protein was confirmed by Western blotting. At 2 months, there was no difference in BW, HW, and blood levels of substrates and insulin between ACC2H−/− (n=4 – 6) and their littermate controls (Con, n=4 – 6). In-vivo cardiac function assessed by echocardiography at 2 and 6 months was also normal in ACC2H−/−. In isolated perfused hearts of comparable contractile performance, 13C NMR spectroscopy showed a 50% increase in the relative contribution of fatty acids to oxidative metabolism in ACC2H−/− vs. Con (74±1% vs. 51±6%, p<0.05, n=3– 4). After 8wks of pressure overload by transverse-aortic constriction (TAC), FAO was markedly decreased (~46%) and glucose utilization increased (~43%) in Con-TAC compared to the sham-operated group while the substrate utilization profile was unchanged in ACC2H−/−-TAC. Cardiac hypertrophy was attenuated in ACC2H−/− as LV posterior wall thickness increased ~40% in TAC-Con (1.5±0.1mm, p<0.05 vs. sham) and only ~20% in ACC2H−/− (1.3±0.1mm, (p=NS). Fractional shortening was reduced by 18% in TAC-Con (p<0.05 vs. sham) and preserved in ACC2H−/−. In summary, we show that fatty acid oxidation can be enhanced via cardiac-specific deletion of ACC2 with no changes in systemic metabolism, cardiac morphology, and function up to 6 months of age. Significant reductions in fatty acid oxidation are present in cardiac hypertrophy and deletion of ACC2 in this model prevents the shift to a fetal metabolic profile without compromising cardiac function.